Fast, simple-to-use assay reveals the 'family tree' of cancer metastases

April 21, 2014
Illustration showing hematogeneous metastasis. Credit: National Cancer Institute

A Massachusetts General Hospital-based research team has developed a simple assay that can reveal the evolutionary relationships between primary tumors and metastases within a patient, information that may someday help with treatment planning.

The process of metastasis – a 's ability to spread to other parts of the body – is still poorly understood. It is not easy to determine whether metastasis began early or late in the development of the primary tumor or whether individual metastatic sites were seeded directly from the original tumor or from an intermediate site. Now a research team has developed a simple assay that can reveal the among various tumor sites within a patient, information that may someday help with treatment planning.

"If we could build a 'family tree' of all cancer nodules in a patient, we could determine how different tumors are related to each other and reconstruct how the cancer evolved," says Kamila Naxerova, PhD, of the Steele Laboratory for Tumor Biology at Massachusetts General Hospital (MGH), corresponding author of the report being published in PNAS Early Edition. "Usually that would require extensive genetic analysis with complex sequencing methods, but our methodology achieves that goal quickly and with minimal experimental effort."

Cancer researchers are just beginning to investigate the extent and significance of genetic differences among tumor cells – either cells within a discrete tumor or between a primary tumor and metastases in other parts of the body. The authors note that there are two different models of metastasis – one in which an advanced primary tumor disseminates late in its development, which would predict little genetic difference between primary and metastatic cells, and another in which metastasis occurs early in , which would predict significant genetic differences in metastatic cells that have evolved separately from those in the primary tumor. Some studies have suggested that the two models apply to different types of cancer, but patient data so far has been limited.

Answering important clinical questions – such as whether genetic diversity is a risk factor for aggressive tumor development or how it relates to treatment resistance – requires analyzing samples from many patients with different types of cancer. Using technologies like whole genome or whole exome (the protein-coding portion of the genome) sequencing requires specialized equipment and advanced data analysis and is still relatively expensive. The approach developed by the MGH team focuses on small areas of the human genome – so-called polyguanine (poly-G) repeats that are particularly susceptible to mutation, with genetic 'mistakes' occurring frequently during cell division. While these mutations do not directly relate to the development or progression of a tumor, they can reveal its lineage – how individual are related to each other.

In the current paper, the authors adapt Poly-G repeat analysis – initially developed to study lineage relationships between single cells in mice – to the study of human cancer for the first time. Analyzing the poly-G profiles of primary and metastatic colon cancer samples from 22 patients revealed that how the primary and metastatic tumors related to each other was different for each patient. In some individuals there were significant genetic differences between tumor sites, suggesting early metastatic spread; in others, there was little difference between a primary tumor and its metastases. The investigators also identified instances in which the genetic profiles of metastases were similar to those of only some cells in the primary tumor, suggesting that those cells were the source of the metastases, and other cases in which the genetic profiles of metastases from the same primary differed depending on their location.

"We found that there are several paths that can lead to metastatic disease," says Naxerova, a postdoctoral research fellow in the Steele Lab. "We are now applying this methodology to address specific clinically relevant questions about the biology of metastasis in larger numbers of patients. The method is fast and inexpensive and should be applicable to other types of tumors than colon cancer."

Co-author Elena Brachtel, MD, from MGH Pathology notes that archival tissues from the files of the department were used for this study. "After diagnostic studies on tissue removed during a patient's operation are completed, the formalin-fixed paraffin tissue blocks are stored for several years. Increasingly, new molecular tests can be performed on tissue that was removed from a patient several years earlier, at a time when these tests were not yet available."

Rakesh K. Jain, PhD, director of the Steele Lab and senior author of the paper, adds, "The assay has many potential clinical applications. For example, it could be used to reliably and quickly distinguish a metastasis from a second, independent tumor. Or it could identify the in situations where multiple lesions are present and it is ambiguous which one is responsible for seeding metastases." Jain is the Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School.

Explore further: Researchers discover disruptions in signaling pathways that enable colorectal cancer cells to form metastases

More information: Hypermutable DNA chronicles the evolution of human colon cancer, PNAS, 2014. www.pnas.org/cgi/doi/10.1073/pnas.1400179111

Related Stories

Researchers discover disruptions in signaling pathways that enable colorectal cancer cells to form metastases

March 24, 2014
Researchers at the University of Freiburg have found switches that colorectal cancer cells use to migrate away from the primary tumor site and to invade neighboring tissue. This migration is the first step in metastasis, ...

Researchers track lethal prostate cancer to determine clonal origin

October 26, 2013
Prostate cancer has variable manifestations, ranging from relatively benign localized tumors to widespread life-threatening metastases. The origin of most prostate cancer metastases can be traced back to the primary tumor; ...

Study reveals mechanisms cancer cells use to establish metastatic brain tumors

February 27, 2014
New research from Memorial Sloan Kettering provides fresh insight into the biologic mechanisms that individual cancer cells use to metastasize to the brain. Published in the February 27 issue of Cell, the study found that ...

How cancer spreads: Metastatic tumor a hybrid of cancer cell and white blood cell

June 27, 2013
Yale Cancer Center scientists, together with colleagues at the Denver Police Crime Lab and the University of Colorado, have found evidence that a human metastatic tumor can arise when a leukocyte (white blood cell) and a ...

Researchers find promising results with local hyperthermia of tumors

March 4, 2014
A combination of iron-oxide nanoparticles and an alternating magnetic field, which together generate heat, have activated an immune system response to tumors in mice according to an accepted manuscript by Dartmouth-Hitchcock ...

Recommended for you

Physical activity could combat fatigue, cognitive decline in cancer survivors

July 25, 2017
A new study indicates that cancer patients and survivors have a ready weapon against fatigue and "chemo brain": a brisk walk.

Breaking the genetic resistance of lung cancer and melanoma

July 25, 2017
Researchers from Monash University and the Memorial Sloan Kettering Cancer Center (MSKCC, New York) have discovered why some cancers – particularly lung cancer and melanoma – are able to quickly develop deadly resistance ...

Anti-cancer chemotherapeutic agent inhibits glioblastoma growth and radiation resistance

July 24, 2017
Glioblastoma is a primary brain tumor with dismal survival rates, even after treatment with surgery, chemotherapy and radiation. A small subpopulation of tumor cells—glioma stem cells—is responsible for glioblastoma's ...

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

No dye: Cancer patients' gray hair darkened on immune drugs

July 21, 2017
Cancer patients' gray hair unexpectedly turned youthfully dark while taking novel drugs, and it has doctors scratching their heads.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.